Björn Stollenwerk

Progression-free survival as a surrogate endpoint in advanced breast cancer

OBJECTIVES Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) for anthracycline (A) and taxane-based (T) chemotherapy in advanced breast cancer (ABC). Using trial-level, meta-analytic approaches, we evaluated PFS as a surrogate endpoint. METHODS A literature review identified randomized, controlled A and T trials for ABC. Progression-based endpoints were classified by prospective definitions. Treatment effects were derived as hazard ratios for PFS (HRPFS) and OS (HROS). Kappa statistic assessed overall agreement. A fixed-effects regression model was used to predict HROS from observed HRPFS. Cross-validation was performed. Sensitivity and subgroup analyses were performed for PFS definition, year of last patient recruitment, line of treatment, and constant rate assumption. RESULTS Sixteen A and fifteen T trials met inclusion criteria, producing seventeen A (n = 4,323) and seventeen T (n = 5,893) trial-arm pairs. Agreement (kappa statistic) between the direction of HROS and HRPFS was 0.71 for A (p = .0029) and 0.75 for T (p = .0028). While HRPFS was a statistically significant predictor of HROS for both A (p = .0019) and T (p = .012), the explained variances were 0.49 (A) and 0.35 (T). In cross-validation, 97 percent of the 95 percent prediction intervals crossed the equivalence line, and the direction of predicted HROS agreed with observed HROS in 82 percent (A) and 76 percent (T). Results were robust in sensitivity and subgroup analyses. CONCLUSIONS This meta-analysis suggests that the trial-level treatment effect on PFS is significantly associated with the trial-level treatment effect on OS. However, prediction of OS based on PFS is surrounded with uncertainty.

Financial incentives in the German statutory health insurance: new findings, new questions

OBJECTIVES This paper presents findings of a mandatory three-year evaluation of a prevention bonus scheme offered in the German Statutory Health Insurance (SHI). Its objective is to describe the rationale behind the programs, analyze their financial impact and discuss their implications on potentially conflicting goals on solidarity and competition. METHODS The analysis included 70,429 insured enrolled in a prevention bonus program in a cohort study. The intervention group and their matched controls were followed for a three-year period. Matching was performed as nearest neighbor matching. The economic analysis comprised all costs relevant for Sickness Funds (SF) in the SHI and was carried out from a SHI perspective. Differences in cost trends between the intervention and the control group were examined applying the paired t-test. RESULTS Regarding mean costs there was a significant difference between the two groups of euro177.48 (90% CI [euro149.73; euro205.24]) in favor of the intervention group. If program costs were considered cost reductions of euro100.88 (90% CI [euro73.12; euro128.63]) were obtained. CONCLUSIONS The uptake of a prevention bonus program led to cost reductions in the intervention group compared to the control group even when program costs were considered. However, the results must be interpreted with caution as in addition to financial aspects, socio-economic and health-status, selection bias and the function and use of bonus programs as marketing tools, as well as their long-term sustainability should be considered in future assessments.

C-Reactive Protein Levels and Post-ICU Mortality in Nonsurgical Intensive Care Patients

BACKGROUND There are no data on the association between acute inflammation during critical illness and long-term mortality in ICU patients. METHODS Nonsurgical patients with an ICU length of stay > 24 h surviving until ICU discharge were included into this prospective, observational, follow-up study. Demographics, chronic diseases, admission diagnosis, the Simplified Acute Physiology Score (SAPS) II, length of ICU stay, maximum C-reactive protein (CRP) levels during the ICU stay (CRPmax), and CRP levels at ICU discharge (CRPdis) were documented. After a follow-up time of 1.88 ± 1.16 years (range, 0.5-4 years), the survival status was determined. RESULTS Seven hundred sixty-five patients were enrolled into the study protocol. One hundred fifty-eight patients (20.7%) died within 0.62 ± 0.88 years after ICU discharge. Cumulative survival rates differed between patients grouped into the CRPmax and CRPdis quartiles. Patients in the first and second CRPmax quartiles had better cumulative survival rates than those in higher CRPmax quartiles (all P < .001). Patients in the first CRPdis quartile had better cumulative survival rates than those in higher CRPdis quartiles (all P < .001). Using adjusted Cox proportional hazards models, both CRPmax and CRPdis were independently associated with post-ICU mortality (both P < .001). Furthermore, the number of chronic diseases (P < .001), age (P < .001), and the SAPS II (P = .03) were associated with post-ICU mortality in both Cox models. CONCLUSIONS CRP levels during critical illness seem independently associated with post-ICU survival in nonsurgical ICU patients. Future research focusing on the association between acute systemic inflammation and post-ICU outcome is warranted in order to improve long-term survival of critically ill patients.

Sex Differences in Treatment Patterns of Six Chronic Diseases: An Analysis from the German Statutory Health Insurance

OBJECTIVE The goal of this study was to investigate gender-specific differences in prevalence, healthcare costs, and treatment patterns in the German Statutory Health Insurance (SHI). METHODS The study analyzed administrative claims data of over 26 million insured with respect to prevalence and cost of illness of six chronic diseases. Insured were identified using the ATC code for medication prescription and ICD-9 code for diagnosis. The influences of gender, age, and comorbidity on cost differences were analyzed via multivariate regression analysis. RESULTS Adjusted for age and comorbidity, gender had a significant influence on both hospital and medication spending. Hospital costs on average were 17.1% (95% CI 14.1; 20.2) higher for men compared with women. Medication spending for men exceeded that for women on average by 13.8% (95% CI 10.9; 16.7). The diagnoses with the highest prevalence were hypertension and heart failure. Women had a higher prevalence of diabetes, coronary artery disease (CAD), heart failure, and hypertension. Medication costs were higher for men in three of five diagnoses and comparable for two diagnoses (diabetes and asthma). Women received more medication prescriptions than men, but on average prescriptions for men were 14%-26% more expensive than prescriptions for women. Regarding treatment patterns men were treated with different drug classes in cardiovascular disease (CVD) compared with women. Total medication spending stratified by diagnosis was highest for diabetes. CONCLUSIONS Gender differences for costs and prescribing patterns for chronic diseases vary disease specifically, but generally men had higher inpatient costs and more expensive medication prescriptions, whereas women had higher numbers of prescriptions.

Preliminary analysis of short term financial implications of a prevention bonus program: First results from the German statutory health insurance

SummaryObjectives:With the implementation of the Health Care Modernization Act in 2004 sickness funds in Germany were given the opportunity to award bonuses to their insured for healthpromoting behavior. The aim of this study was to investigate the financial implications of a prevention bonus program from a sickness fund perspective.Method:The investigation was designed as a controlled cohort study (matched pair study) comprising 70,429 members in each group. Matching criteria were sex, postal code, insurance status, and cost categories for health care utilization. Insured opted into the program on a voluntary basis. The program consisted of interventions featuring primary prevention, modest exercise and immunization. Differences in cost trends between the two groups were examined using the paired t-test.Results:A reduction in mean costs of 241.11 € per active member for the year 2005 (90 % CI = 348.70, 133.52; p-value < 0.001) could be achieved in the intervention group compared to the control group. When costs for the implementation of the program and the bonus payments were taken into account, there was a saving of 97.14 € per active member for the year 2005.Conclusions:Preliminary results of a prevention bonus program in the German Statutory Health Insurance suggest a decrease in mean health care spending per enrollee. These effects may increase with time as long term effects of prevention become effective. However, further research is needed to understand how much of these short term cost reductions can be attributed to the program itself rather than to possible confounders or volunteer bias and how the short term savings may be accrued.

Prognostic value, clinical effectiveness, and cost-effectiveness of high-sensitivity C-reactive protein as a marker for major cardiac events in asymptomatic individuals: A health technology assessment report

OBJECTIVES The aim of this study was to compare the predictive value, clinical effectiveness, and cost-effectiveness of high-sensitivity C-reactive protein (hs-CRP)-screening in addition to traditional risk factor screening in apparently healthy persons as a means of preventing coronary artery disease. METHODS AND RESULTS The systematic review was performed according to internationally recognized methods. Seven studies on risk prediction, one clinical decision-analytic modeling study, and three decision-analytic cost-effectiveness studies were included. The adjusted relative risk of high hs-CRP-level ranged from 0.7 to 2.47 (p < .05 in four of seven studies). Adding hs-CRP to the prediction models increased the areas under the curve by 0.00 to 0.027. Based on the clinical decision analysis, both individuals with elevated hs-CRP-levels and those with hyperlipidemia have a similar gain in life expectancy following statin therapy. One high-quality economic modeling study suggests favorable incremental cost-effectiveness ratios for persons with elevated hs-CRP and higher risk. However, many model parameters were based on limited evidence. CONCLUSIONS Adding hs-CRP to traditional risk factors improves risk prediction, but the clinical relevance and cost-effectiveness of this improvement remain unclear.

Effects of a nurse-based case management compared to usual care among aged patients with myocardial infarction: results from the randomized controlled KORINNA study

BackgroundTransition from hospital to home is a critical period for older persons with acute myocardial infarction (AMI). Home-based secondary prevention programs led by nurses have been proposed to facilitate the patients’ adjustment to AMI after discharge. The objective of this study was to evaluate the effects of a nurse-based case management for elderly patients discharged after an AMI from a tertiary care hospital.MethodsIn a single-centre randomized two-armed parallel group trial of patients aged 65 years and older hospitalized with an AMI between September 2008 and May 2010 in the Hospital of Augsburg, Germany, patients were randomly assigned to a case management or a control group receiving usual care. The case-management intervention consisted of a nurse-based follow-up for one year including home visits and telephone calls. Key elements of the intervention were to detect problems or risks and to give advice regarding a wide range of aspects of disease management (e.g. nutrition, medication). Primary study endpoint was time to first unplanned readmission or death. Block randomization per telephone call to a biostatistical center, where the randomization list was kept, was performed. Persons who assessed one-year outcomes and validated readmission data were blinded. Statistical analysis was based on the intention-to-treat approach and included Cox Proportional Hazards models.ResultsThree hundred forty patients were allocated to receive case-management (n=168) or usual care (n=172). The analysis is based on 329 patients (intervention group: n=161; control group: n=168). Of these, 62% were men, mean age was 75.4 years, and 47.1% had at least either diabetes or chronic heart failure as a major comorbidity. The mean follow-up time for the intervention group was 273.6 days, and for the control group it was 320.6 days. During one year, in the intervention group there were 57 first unplanned readmissions and 5 deaths, while the control group had 75 first unplanned readmissions and 3 deaths. With respect to the endpoint there was no significant effect of the case management program after one year (Hazard Ratio 1.01, 95% confidence interval 0.72-1.41). This was also the case among subgroups according to sex, diabetes, living alone, and comorbidities.ConclusionsA nurse-based management among elderly patients with AMI had no significant influence on the rate of first unplanned readmissions or death during a one-year follow-up. A possible long-term influence should be investigated by further studies.Clinical trial registrationISRCTN02893746

Transparency vs. closed-door policy: Do process characteristics have an impact on the outcomes of coverage decisions? A statistical analysis

The aim of this study was to analyze influences of process- and technology-related characteristics on the outcomes of coverage decisions. Using survey data on 77 decisions from 13 countries, we examined whether outcomes differ by 14 variables that describe components of decision-making processes and the technology. We analyzed the likelihood of committees covering a technology, i.e. positive (including partial coverage) vs. negative coverage decisions. We performed non-parametric univariate tests and binomial logistic regression with a stepwise variable selection procedure. We identified a negative association between a positive decision and whether the technology is a prescribed medicine (p=0.0097). Other significant influences on a positive decision outcome included one disease area (p=0.0311) and whether a technology was judged to be (cost-)effective (p<0.0001). The first estimation of the logistic regression yielded a quasi-complete separation for technologies that were clearly judged (cost-)effective. In uncertain decisions, a higher number of stakeholders involved in voting (odds ratio=2.52; p=0.03) increased the likelihood of a positive outcome. The results suggest that decisions followed the lines of evidence-based decision-making. Despite claims for transparent and participative decision-making, the phase of evidence generation seemed most critical as decision-makers usually adopted the assessment recommendations. We identified little impact of process configurations.

Communicating the parameter uncertainty in the IQWiG efficiency frontier to decision-makers.

The Institute for Quality and Efficiency in Health Care (IQWiG) developed—in a consultation process with an international expert panel—the efficiency frontier (EF) approach to satisfy a range of legal requirements for economic evaluation in Germanys statutory health insurance system. The EF approach is distinctly different from other health economic approaches. Here, we evaluate established tools for assessing and communicating parameter uncertainty in terms of their applicability to the EF approach. Among these are tools that perform the following: (i) graphically display overall uncertainty within the IQWiG EF (scatter plots, confidence bands, and contour plots) and (ii) communicate the uncertainty around the reimbursable price. We found that, within the EF approach, most established plots were not always easy to interpret. Hence, we propose the use of price reimbursement acceptability curves—a modification of the well-known cost-effectiveness acceptability curves. Furthermore, it emerges that the net monetary benefit allows an intuitive interpretation of parameter uncertainty within the EF approach. This research closes a gap for handling uncertainty in the economic evaluation approach of the IQWiG methods when using the EF. However, the precise consequences of uncertainty when determining prices are yet to be defined.

Uncertainty assessment of input parameters for economic evaluation: Gauss's error propagation, an alternative to established methods.

In decision modeling for health economic evaluation, bootstrapping and the Cholesky decomposition method are frequently used to assess parameter uncertainty and to support probabilistic sensitivity analysis. An alternative, Gauss’s error propagation law, is rarely known but may be useful in some settings. Bootstrapping, the Cholesky decomposition method, and the error propagation law were compared regarding standard deviation estimates of a hypothetic parameter, which was derived from a regression model fitted to simulated data. Furthermore, to demonstrate its value, the error propagation law was applied to German administrative claims data. All 3 methods yielded almost identical estimates of the standard deviation of the target parameter. The error propagation law was much faster than the other 2 alternatives. Furthermore, it succeeded the claims data example, a case in which the established methods failed. In conclusion, the error propagation law is a useful extension of parameter uncertainty assessment.